Methylglutaconyl-CoA hydratase, mitochondrial
Function
Catalyzes the fifth step in the leucine degradation pathway, the reversible hydration of 3-methylglutaconyl-CoA (3-MG-CoA) to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) (PubMed:11738050, PubMed:12434311, PubMed:12655555, PubMed:16640564). Can catalyze the reverse reaction but at a much lower rate in vitro (PubMed:16640564). HMG-CoA is then quickly degraded by another enzyme (such as HMG-CoA lyase) to give acetyl-CoA and acetoacetate (PubMed:16640564). Uses other substrates such as (2E)-glutaconyl-CoA efficiently in vitro, and to a lesser extent 3-methylcrotonyl-CoA (3-methyl-(2E)-butenoyl-CoA), crotonyl-CoA ((2E)-butenoyl-CoA) and 3-hydroxybutanoyl-CoA (the missing carboxylate reduces affinity to the active site) (PubMed:16640564). Originally it was identified as an RNA-binding protein as it binds to AU-rich elements (AREs) in vitro (PubMed:7892223). AREs direct rapid RNA degradation and mRNA deadenylation (PubMed:7892223). Might have itaconyl-CoA hydratase activity, converting itaconyl-CoA into citramalyl-CoA in the C5-dicarboxylate catabolism pathway (PubMed:29056341). The C5-dicarboxylate catabolism pathway is required to detoxify itaconate, an antimicrobial metabolite and immunomodulator produced by macrophages during certain infections, that can act as a vitamin B12-poisoning metabolite (PubMed:29056341).
Involvement in disease
3-methylglutaconic aciduria 1
MGCA1
An inborn error of leucine metabolism. It leads to an autosomal recessive syndrome with variable clinical phenotype, ranging from delayed speech development to severe psychomotor retardation, coma, failure to thrive, metabolic acidosis and dystonia. MGCA1 can be distinguished from other forms of MGCA by the pattern of metabolite excretion: 3-methylglutaconic acid levels are higher than those detected in other forms, whereas methylglutaric acid levels are usually only slightly elevated and there is a high level of 3-hydroxyisovaleric acid excretion (not present in other MGCA forms).
None
The disease is caused by variants affecting the gene represented in this entry.
Pathway
Amino-acid degradation; L-leucine degradation; (S)-3-hydroxy-3-methylglutaryl-CoA from 3-isovaleryl-CoA: step 3/3.
Sequence Similarities
Belongs to the enoyl-CoA hydratase/isomerase family.
Cellular localization
- Mitochondrion
Alternative names
3-MG-CoA hydratase, AU-specific RNA-binding enoyl-CoA hydratase, Itaconyl-CoA hydratase, AU-binding protein/enoyl-CoA hydratase, AUH